Array与IL-2抗癌效应的发现

[编者的话]

美国国家癌症研究所的科学家们日前在名为Beyond Genome 2001的学术会议上报告了他们的研究成果——借助于芯片和生物信息学分析的力量，他们首次揭示了IL-2抗癌效应的机制。

by Roberta Friedman

Interleukin-2 has the ability to recruit an inflammatory response that could prompt the body's immune system to reject certain tumors, researchers at the US National Cancer Institute reported today at the Beyond Genome 2001 meeting. This new information comes from microarray studies that reveal the mechanism of IL-2's anticancer effects for the first time.

An inflammatory mediator made by white blood cells, IL-2 can be effective in about 10% of patients with metastatic kidney cancer or melanoma. It may also boost response rates in trials of other therapies, such as a patient's own tumor-infiltrating lymphocytes, or vaccines of melanoma antigen. The cytokine ramps up the production of inflammation markers in both circulating immune cells and tumor cells, the array data suggest.

"What we see in the peripheral blood, which is basically all these inflammatory cytokines, and also inflammatory markers for adhesion and migration, we also see at the tumor site," said Monica Panelli, a researcher at the National Cancer Institute in Bethesda, Maryland. Panelli told BioMedNet News that a tumor might grow unnoticed if a patient's immune genes do not kick in or if tumor-infiltrating lymphocytes are not turned on properly, and IL-2 might correct that situation.

The researchers focused on 75 genes with the highest median ratio and 75 with the lowest median ratio of expression between the reference sample, before IL-2 was given, and the test sample, three hours after the IL-2 treatment. Treatment with the cytokine up-regulated cell surface, adhesion, and inflammatory genes and down-regulated a group of cell cycle and metabolic protein genes. The researcher's new-found ability to amplify the scanty material taken by fine needle aspiration enabled the array data.

The amplification method "is very nice," said Francesco Falciani, senior scientist with Lorantis, Ltd. of the UK. Falciani, who presented microarray data revealing genes associated with rheumatoid arthritis, said the array data show a "common mechanism of how cells respond to cytokines," and the NCI research "fits very well with what I am doing."

Bioinformatics scientist Tim Dexter, who has just begun work with the Breakthrough Centre of the Institute of Cancer Research in London, says that the study, while done well, begs for a look at the difference between responders and non-responders to the therapy. In collaboration with the Royal Marsden hospitals, Dexter wants to find "the predictive method" to look at breast cancer microarrays.

One problem plagues the NCI microarray sample: Of the six recruited to that study, only one had had a clinical response to the treatment. This reflects the poor response rate to the treatment in general: In the cancer study itself, of 409 consecutive patients with either metastatic renal carcinoma or melanoma, only 7% had complete responses and another 8% had partial responses.

The researchers have yet to correlate the inflammatory response to IL-2 with any clinical response to the treatment. "We just wanted to study the pathway of IL-2," Panelli said. Because IL-2 causes lymphocyte counts to decrease, she said, "we are looking at how many of the apoptosis genes we see after IL-2 infusions."

Non-responders might yet yield predictive differences for therapy, says Panelli. Research by the NCI group that might help predict who responds to melanoma vaccinations is currently under review for publication.